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Bhasin et al. J Transl Genet Genom 2024;8:55-76 https://dx.doi.org/10.20517/jtgg.2023.46 Page 69

Fortunately, newer-generation BiTEs have optimized drug delivery with half-life-extended (HLE)
formulations. While BiTE therapy boasts the potential of “off-the-shelf” manufacturing, allowing for cost-
effective drug production without the cost or time needed for individual customization, further studies are
necessary to identify appropriate TAAs in hopes of restricting target effect further improving safety
profiles [26,28,35,74,143,144] . CAR-T therapy has faced similar hurdles, but specific limitations include the necessity
to individually tailor therapy for patients, which is an expensive and time-consuming process, ultimately
limiting availability. The need for prior lymphodepletion also poses a significant risk of infection and
immunosuppression in a high-risk patient population [26,74,145,146] . Furthermore, traditional CAR-T delivery is
not compatible with future off-the-shelf drug manufacturing. Both classes of T-cell redirecting therapies
face the challenge of acquired treatment resistance due to TAA downregulation as an immune evasion
mechanism. Combination therapy with ICIs and targeting multiple TAAs simultaneously have been
proposed as strategies to overcome this barrier [26,28,35,74] . Moreover, the clinical data at hand surrounding T-
cell redirecting therapies come from studies conducted in heavily pre-treated castration-resistant patient
populations, who typically harbor an exhausted T-cell phenotype with a predominance of T-regulatory cell
subsets within the TME [143,147,148] . As such, trial design with implementation of these therapies earlier in the
natural history of the disease may prove the novel immunotherapies to be more efficacious than current
data suggests.

The strong interest in prostate cancer immune-oncology has spurred the creation of several new drug
constructs, including dual affinity retargeting bispecific antibodies (DART), simultaneous multiple
interaction T-cell engagers (SMITE), CAR-NK, bispecific killer engagers (BiKE), and tri-specific killer
engager agents (TriKE). DART and SMITE therapy are extensions of BiTE therapy that attempt to
simultaneously target multiple TAAs in order to avoid acquired treatment resistance that is the experience
commonly seen with BiTE administration in hematologic malignancies [26,66] . Alternatively, CAR-NK therapy
is similar to CAR-T therapy; however, this treatment modality functions by proliferation and activation of
NK cells rather than T-cells. In preclinical models, CAR-NK cells demonstrate the ability to retain their
innate ability to identify target cells with downregulated TAAs, while also demonstrating targeted tumor
cellular lysis with dual target antigen domains. NK cells also have a shorter life span compared to T- cells,
which is suspected to decrease drug-related toxicities. Furthermore, this construct boasts the possibility of
off-the-shelf manufacturing, as drug creation does not require individual customization [66,149] . BiKE therapy
is mechanistically similar to BiTE therapy, but the anti-CD3 domain is replaced by anti-CD16 to target NK
cell activation instead of T-cells. TriKE follow the same mechanistic principles but theoretically further
enhance NK cell activation and function [66,149-151] . Additionally, cancer vaccine development has undergone a
new resurgence with the employment of novel TAAs and new vaccine formulations that aim to function
with both humoral and adaptive immunity with the intention of antigen spread and possible synergistic
[152]
therapeutic efficacy with ICI administration . Antigen-drug conjugate (ADC) therapies are rapidly
emerging agents composed of a monoclonal antibody with a covalently linked cytotoxic load, garnering
increasing attention in immunotherapy in recent times. ADCs are actively being designed to target many of
[153]
the discussed TAAs, as well as other antigen targets, with promising preliminary results . Additional
antigen targets with encouraging immunotherapy advancements undergoing active study and development
are referenced in Table 3.

CONCLUSION
Immunotherapy in prostate cancer offers an opportunity for innovative treatment approaches with
encouraging therapeutic potential. T-cell redirecting therapies have shown robust antitumor activity
correlating with immune activation in preclinical and early-phase clinical trials. The therapeutic potential of
these therapies relies on the emergence of TAAs for which next-generation BiTE and CAR-T constructs